The therapy method of tumor arterial embolism is to inject an embolus into micro-arteries, causing mechanical blocking and inhibiting tumor growth. In 1981 Kato debuted this therapy method combining chemotherapeutic drugs with embolism materials for treating malignant tumors unsuitable for surgical operations. In recent years this method has been applied to treat hepatocarcinoma, renal cancer, tumors in pelvis and head and neck showing effective results. However, this method suffers from a high relapse rate.
Microsphere preparations are particles made by medications and proper auxiliary materials through micro-encapsulation technology. Effectiveness of a microsphere for embolism purposes depends on diameter, degrading speed of skeleton of the microsphere, drug-carrying speed, and drug release speed. The drug-containing microsphere preparations can block micro-vessels, which supported the carcinoma, and the embolism can supply anti-tumor drugs to tumor-targeted area and kill cancerous cells, which enables the drugs to be oriented and controllable. This kind of method for drug administration is able to improve drug distribution in vivo and pharmacokinetic features, increase bioavailability of drugs, improving treatment effect, and alleviate toxic or side effects.
Microsphere preparations for tumor arterial embolism should have characteristics as followings: powerful enough to embolism, strong mechanically and stable physically and chemically, the drug can be released slowly and persistently, maintaining a therapeutic concentration in the targeted areas; the drug carrier can be eroded by the receiver, and is biocompatible, free from immunogenicity, and free from harms to body even lingering around the targeted areas for a long time.
Sodium alginate is a sodium polysaccharide extracted from natural alga, forming sticky gel when solved in water. Under presence of calcium ion, its macromolecular chains can cross link and solidify. This kind of microsphere is a kind of biological derived materials having good biocompatibility. Accordingly, it can be processed to be a round solid microsphere with different sizes as desired. Under the phosphoric acid buffer condition in animal vessels, calcium ions seep out and the microspheres degrade in the form of molecular chains within 5-10 days or 3-6 months. The degradation products are mannitose and gulose being unable to be absorbed by the body. Size and evenness of the microspheres are controllable and fast bulging once they enter into vessels, let alone they are good at location. Thus sodium alginate is made as microspheres that wrap anti-tumor drugs and/or encapsulate liposome-wrapped cytokines, releasing the drugs/cytokines to specific organs on specific times for local immunochemotherapy of tumors after being administered to the target organs.
Immunotherapy can eradicate residual tumor cells and small metastatic micro-tissues and early-stage tumors, and prevent metastasis and relapse, acting as an effective auxiliary specific therapy. Cytokines play an important role in modulating immunity, fighting against infection and tumor.
Interleukin-2 (IL-2) is able to transform static pre-cytotoxic T cells to cytotoxic T cells, maintain growth of lymphokine-activated killer (LAK) cells and TIL cells, enhance non-specific killing of tumor cells via activated macrophages, and is produced in lymphokine-activated killer (LAK) cells. A combination of solo or infusion of killer cells can reduce metastasis and relapse of tumors. IFN-Γ is produced by a kind of activated T cell or by Natural Killer (NK) Cells, preventing a wide variety of tumor cells from propagating, enhancing immunogenicity of tumor cells and modulating cell-mediated immunity, including stimulating propagation of NK and monocyte, maintaining persistent TH1 type cell reaction, inducing production of IL-12, forming a cycle of positive feedback. TUMOR NECROSIS FACTOR is versatile fighting against tumors by taking cytotoxic effects onto some certain cells, causing necrosis of newborn vessels of tumor, and/or causing pathological blood coagulation via enhancing blood coagulation of endothelial cells of tumor vessels blocking blood supply to tumor tissues. In addition, TUMOR NECROSIS FACTOR can kill tumor cells by activating some hydrolase.
Lab and clinical researches reveal that cytokines such as interleukin-2 (IL-2), interferon (IFN-α, β and γ) and tumor necrosis factor (TNF) are able to fight against tumors, more effective when used in cohort. Cytokines and chemotherapeutic drugs can take synergistic effect or enhance therapeutic effect when they are used together. Research also reveal that TNF-α, IFN-α, IFN-γ, and IL-2, etc. can help tumors more sensitive to chemotherapeutic drugs.
Besides inducing differentiation of tumor cells, interferon also amplify sensitizing effects of amuycin (ADM), 5-FU, cisplatin, vincaleucoblastine, and alkylating agents. In practicing immunotherapy, IFN-α is often used in combination with IL-2, which is superior to using either of them exclusively, causing an effect of 1+1>2. A triple use of IFN-α, IL-2 and TNF-α can well assist chemotherapeutic drugs. Cytokines also modulate expression of multiple drug resistance gene (MDR1), enhancing cytotoxicity of MDR1-related amycin and vincristine, showing a time and concentration dependence. Highly concentrated cytokines can reverse MDR1 significantly, enhancing sensitivity to chemotherapy of tumor cells, improving micro-environment of tumors, and enhancing body's immunoresponse to tumor cells, owing to which the tumors can be contained. Thus cytokines combined with chemotherapy can be applied to chemotherapy-resistance tumors.
Some chemotherapeutic drugs such as CTX, MMC, ADM and DDP can help cytokines such as IL-2 more effective against tumors, taking synergistic effect or improving therapeutic effect. Along with chemotherapy, administration of immunotherapy can alleviate side effects of chemotherapy, improve host tolerance, increase tumor inhibition rate, reduce local relapse and far-reaching metastasis rate. On the other hand, immunotherapy can enhance the effect of chemotherapy. Therefore, it is reasonable to jointly use many ways to fight against tumors, and immunochemotherapy is an important way to treat tumors.
Professor Tadatsugu Taniguchi of Tokyo University of Japan recently published his research on a combined use of interferon and anti-tumor agents on Nature e-magazine, reporting that interferon can up level expression of P53 protein in cells. A combined use of interferon with radiotherapy or chemotherapy is superior to using chemotherapy or radiotherapy exclusively, helping to reduce dosage of anti-tumor agents and alleviate side effects. British Windbichler GH et al. conducted a prospective study (a randomized three-phase clinical trial) on 148 IC-IV phase primary ovary cancer patients who have undergone tumor-cell-number-dwindling operation, administering them a combination of interferon-Γ and CP. The author held that addition of interferon-Γ into first-line chemotherapeutic drugs is able to prolong progression-free survival cycle of tumors.
Owing to side effects of cytokines in vivo, application of the cytokines are limited. IL-2 has a short half-life and poor stability in vivo, and large dosage of IL-2 can compromise hepatic and renal functions and cause lung capillary leaking syndrome. TNF-α can be discharged by kidney and decomposed by some enzymes, having short half-life, being unstable in vivo, poorly tolerable by human beings. Side effects of TNF-α can be fever, nausea, vomiting, headache, even server hypotension and shock.
How to reasonably use cytokines is very meaningful. Current measures to properly use cytokines include: (1) jointly using various cytokines (IFN, IL-2) or using cytokines in combination with chemotherapeutic drugs in order to lower dosage of cytokines; (2) change structure of cytokines trying to obtain cytokines that are highly effective but less toxic, such as developing derivatives of TNF. (3) Using liposome capsule can significantly enhance stability and in vivo bioavailability of cytokines, elongate half-life, alleviate toxicity, target site more precisely, increase bioactivity, and improve anti-tumor and immunomodulation functions. (4) Change routes and approaches for administration of cytokines
Arterial intervention is an important approach to treat solid organs. Drugs sent to a local site of tumor tissues via arterial embolism can directly distribute drugs to the tumor tissues, maintaining a high drug concentration locally, activating functions of effector cells, more powerful fighting against tumors. Localized immunotherapy can overcome immunosuppression caused by tumors, easily spark immune memory and immune response, and enjoy less systemic side effects and safer usage. Locally used IFN can help a high-concentration drug to directly contact tumor tissues, enhance infiltration of macrophages and lymphocytes into lesions and their surroundings, and strongly destroy tumor cells. For exposed tumors direct injection of IFN into body of papilloma, breast cancer or cervical cancer can achieve satisfactory short-range effect.
Gaojian et al. treated 62 HBsAg-positive hepatocarcinoma patients using a combination of IFN-α 1b with chemotherapy embolism via hepatic artery (TACE) observing therapeutic effect and prognosis. The results showed that a cohort of IFN+TACE can inhibit reproduction of hepatitis B virus, alleviate hurt to the liver caused by interventional chemotherapy, decrease in-liver relapse rate, increase survival rate and reduce side effect. Pan Tiejun et al. treated malignant renal tumors using embolism therapy with a cohort of TNF and IL-2, comparing results with patients receiving renal embolism exclusively. His results showed that tumor tissues injected with cytokines had much more infiltration of lymphocytes and macrophages, and ends of renal veins were stuffed with necrotic tumor cells, and no tumor cells survived under the masses. His results suggest that combined use of TNF and IL-2 on the one hand causes ischemia and death of tumor tissues by blocking blood supply to the tissues, and on the other hand activates macrophages, recognizing and killing tumor cells and reducing inducing of drug resistance for targeted cells. Cao Zeyi et al. observed activity of TIL and NK by irrigating IL-2 via pelvic retroperitoneal space, probing the feasibility of biotherapy. His results showed that the cohort IL-2+5-FU is different from either solo 5-FU or solo IL-2 in CD3, CD4, CD8, CD25 and NK, indicating irrigating IL-2 via pelvic retroperitoneal space can activate TIL and NK of tumor tissues.
Microsphere preparations are made with certain drugs and auxiliary materials using micro-encapsulation technology. Administration of drugs in the form of a microsphere helps the drugs be site targeted and release controllable. This kind of method for drug administration is able to improve drug distribution in vivo and pharmacokinetic features, increase bioavailability of drugs, improving treatment effect, and alleviate toxic or side effects. Chemotherapeutic-drug-containing microspheres via arterial embolism can cluster in arterial vessels around the lesion blocking blood supply to the lesion and releasing drug persistently, effectively inducing apoptosis and causing ischemic and anoxia and death of cancerous cells.